Project

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The molecular mechanisms underlying UVB-induced caspase-1-dependent apoptosis in keratinocytes

English title The molecular mechanisms underlying UVB-induced caspase-1-dependent apoptosis in keratinocytes
Applicant Beer Hans-Dietmar
Number 132450
Funding scheme Project funding
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Molecular Biology
Start/End 01.10.2010 - 30.04.2014
Approved amount 375'000.00
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All Disciplines (3)

Discipline
Molecular Biology
Experimental Cancer Research
Immunology, Immunopathology

Keywords (6)

Inflammasome; UV irradiation; Apoptosis; caspase-1; keratinocyte; epidermis

Lay Summary (English)

Lead
Lay summary
The protease caspase-1 is crucially involved in innate immunity and in the activation of aquired immunity. Therefore, it plays a key role in inflammation and disease. It cleaves and thereby activates the proinflammatory cytokines prointerleukin(IL)-1b and -18. In addition, we recently showed that caspase-1 activity is required for unconventional secretion of active IL-1b, IL-18, and of many other leaderless proteins, which are involved in inflammation, repair and apoptosis. Upon infection with certain pathogens, environmental insults or endogenous danger signals, caspase-1 is activated in innate immune complexes called inflammasomes. In contrast to several of its family members, endogenous caspase-1 is considered not to be required for apoptosis. The protease is, however, involved in pyroptosis, a recently identified pathogen-induced form of cell death distinct from necrosis and apoptosis.We have recently shown that UVB-irradiated keratinocytes secrete large amounts of active IL-1?, which is dependent on the expression of inflammasome proteins. Most importantly, sunburn in mice lacking expression of caspase-1 is significantly reduced in comparison to wildtype mice demonstrating that caspase-1 expression is also required in vivo for UVB-induced inflammation in the skin. In addition, UV irradiation causes cell death and apoptosis in vitro in keratinocytes and in vivo in the skin. Although these dead keratinocytes cannot develop to tumor cells UV irradiation is the major cause for skin cancer.In this project we will analyze whether and how caspase-1 and other inflammasome proteins are involved in UVB-induced apoptosis. We will mainly use UVB-irradiated human primary keratinocytes as a model system as well as wildtype and caspase-1 knockout mice. A major goal will be the identification of binding partners and substrates of caspase-1, which may be involved in the induction of apoptosis and cell death upon UV irradiation.We expect that this project will contribute to a better understanding of the molecular mechanisms of UV-induced apoptosis in keratinocytes and in other cell types. This may allow the development of novel strategies to prevent UV-induced skin cancer and to treat existing tumors of the skin.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Caspase-1 activity is required for UVB-induced apoptosis of human keratinocytes
Sollberger Gabriel, Garstkiewicz Martha, Strittmatter Gerhard Egeon, auf dem Keller Ulrich, French Lars Einar, Beer Hans-Dietmar (2015), Caspase-1 activity is required for UVB-induced apoptosis of human keratinocytes, in Journal of Investigative Dermatology, 135, 1395-1404.
Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice.
Schäfer Matthias, Willrodt Ann-Helen, Kurinna Svitlana, Link Andrea S, Farwanah Hany, Geusau Alexandra, Gruber Florian, Sorg Olivier, Huebner Aaron J, Roop Dennis R, Sandhoff Konrad, Saurat Jean-Hilaire, Tschachler Erwin, Schneider Marlon R, Langbein Lutz, Bloch Wilhelm, Beer Hans-Dietmar, Werner Sabine (2014), Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice., in EMBO molecular medicine, 6(4), 442-57.
Caspase-1: the inflammasome and beyond.
Sollberger Gabriel, Strittmatter Gerhard E, Garstkiewicz Martha, Sand Jennifer, Beer Hans-Dietmar (2014), Caspase-1: the inflammasome and beyond., in Innate immunity, 20(2), 115-25.
Caspase-1: the inflammasome and beyond.
Sollberger Gabriel, Strittmatter Gerhard E, Garstkiewicz Martha, Sand Jennifer, Beer Hans-Dietmar (2014), Caspase-1: the inflammasome and beyond., in Innate immunity, 20(2), 115-25.
Aldara activates TLR7-independent immune defence.
Walter Anne, Schäfer Matthias, Cecconi Virginia, Matter Claudia, Urosevic-Maiwald Mirjana, Belloni Benedetta, Schönewolf Nicola, Dummer Reinhard, Bloch Wilhelm, Werner Sabine, Beer Hans-Dietmar, Knuth Alexander, van den Broek Maries (2013), Aldara activates TLR7-independent immune defence., in Nature communications, 4, 1560-1560.
Caspase-4 is required for activation of inflammasomes.
Sollberger Gabriel, Strittmatter Gerhard E, Kistowska Magdalena, French Lars E, Beer Hans-Dietmar (2012), Caspase-4 is required for activation of inflammasomes., in Journal of immunology (Baltimore, Md. : 1950), 188(4), 1992-2000.
Interleukin-1, inflammasomes, autoinflammation and the skin.
Contassot Emmanuel, Beer Hans-Dietmar, French Lars E (2012), Interleukin-1, inflammasomes, autoinflammation and the skin., in Swiss medical weekly, 142, 13590-13590.
Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18
Roth W (2012), Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18, in J Cell Sci, 125(Pt22), 5269-79.
Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells.
Winter Meike, Beer Hans-Dietmar, Hornung Veit, Krämer Ursula, Schins Roel P F, Förster Irmgard (2011), Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells., in Nanotoxicology, 5(3), 326-40.
Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression.
Fettelschoss Antonia, Kistowska Magdalena, Leibundgut-Landmann Salomé, Beer Hans-Dietmar, Johansen Pål, Senti Gabriela, Contassot Emmanuel, Bachmann Martin F, French Lars E, Oxenius Annette, Kündig Thomas M (2011), Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression., in Proceedings of the National Academy of Sciences of the United States of America, 108(44), 18055-60.
The Inflammasomes in Autoinflammatory Diseases with Skin Involvement.
Beer Hans-Dietmar, Contassot Emmanuel, French Lars E, The Inflammasomes in Autoinflammatory Diseases with Skin Involvement., in The Journal of investigative dermatology.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ESDR Meeting Venice Poster Caspase-1 and UVB-induced apoptosis of human keratinocytes 19.09.2012 Venice, Italy Beer Hans-Dietmar; Sollberger Gabriel;


Associated projects

Number Title Start Funding scheme
126141 Unconventional Protein Secretion (EMRC/ECORES/08-EUROMEMBRANE) 01.01.2009 Project funding (special)
197426 The upstream and downstream regulation of the NLRP1 inflammasome in human keratinocytes 01.10.2020 Project funding
117959 Roles of EBBP and its binding partner caspase-1 in the UV-induced alternative protein secretion pathway of skin-derived cells 01.10.2007 Project funding

Abstract

The protease caspase-1 is crucially involved in innate immunity and in the activation of aquired immunity. Therefore, it plays a key role in inflammation and disease. It cleaves and thereby activates the proinflammatory cytokines prointerleukin(IL)-1ß and -18. In addition, we recently showed that caspase-1 activity is required for unconventional secretion of active IL-1ß, IL-18, and of many other leaderless proteins, which are involved in inflammation, repair and apoptosis. Upon infection with certain pathogens, environmental insults or endogenous danger signals, caspase-1 is activated in innate immune complexes called inflammasomes. In contrast to several of its family members, endogenous caspase-1 is considered not to be required for apoptosis. The protease is, however, involved in pyroptosis, a recently identified pathogen-induced form of cell death distinct from necrosis and apoptosis.We have evidence that UVB-induced apoptosis of keratinocytes in vitro in human primary cells and in vivo in mice is strongly dependent on caspase-1 expression and activity. The inflammasome-dependent caspase-1 activation and unconventional protein secretion supports survival of keratinocytes through secretion of proapoptotic proteins such as Bid and caspase-3. In addition, it protects keratinocytes via secretion of IL-1, which activates NF-?B in an autocrine or paracrine manner. Nevertheless, a significant fraction of the cells dies during a second phase by apoptosis, possibly due to a direct activation of caspase-3 by caspase-1. This fraction of apoptotic cells is strongly reduced upon knockout or knockdown of caspase-1 expression or upon inhibition of caspase-1 activity. Most interestingly, this caspase-1-dependent apoptosis occurs independently of other inflammasome proteins.In this proposal we describe experiments aiming to further test our hypothesis of a role of caspase-1 in UVB-induced apoptosis in keratinocytes. In addition, we will examine the prosurvival effect of unconventional protein secretion, particularly the consequences of IL-1a and -ß secretion in vitro and in vivo in mice. An important question that we will experimentally address is whether caspase-1-dependent apoptosis occurs only upon UVB-irradiation in keratinocytes or whether it represents a more general stress-induced pathway. For the characterization of the molecular mechanism of initiation and execution of UVB-induced caspase-1-dependent apoptosis we will apply an siRNA- and affinity purification-based proteomics approach with and without iTRAQ labeling of the purified proteins. Results from us and from others suggest that caspase-1 is a tumor promoter via secretion of IL-1 and other leaderless proteins, but it may also act as tumor suppressor through its proapoptotic properties. We will examine this hypothesis in an experimental cancer model.IL-1 and caspase-1 are involved in several human skin diseases. In addition, UV is the main cause of non-melanoma skin cancers and most likely also contributes to the development of melanomas, the deadliest form of skin cancer. Therefore, the experiments suggested in this proposal are not only important for basic research but may also result in the development of new strategies to prevent and treat inflammatory and malignant skin diseases.
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